We have developed a novel method of genetically engineering virulence- attenuated strains of picornaviruses including polio- and Mego viruses. Through this novel method, it is possible to create replication-competent recombinant viruses that stably carry and express genetic sequences derived from other pathogenic agents. The objective of this proposal is to evaluate the potential of recombinant picornaviruses expressing antigens derived from the human immunodeficiency virus (HIV) and the simian immunodeficiency virus (SIV) to serve as safe and effective vaccines for the prevention of infection by these immunosuppressive lentiviruses. HIV infection is spreading worldwide at a remarkable rate, and projects of the future course of the pandemic are alarming. As a result, the development of an efficacious vaccine to prevent HIV infection has become an essential priority. The vast majority of cases of infection to date have resulted from exposure to HIV during sexual intercourse, with transmission of the virus occurring across mucosal surfaces. A primary challenge confronting HIV vaccine development efforts is the successful interruption of viral transmission through the effective induction of mucosal immune responses. Unfortunately, most candidate HIV vaccines preferentially induce systemic but not mucosal immune responses and are unlikely to prevent infection via the most common routes of exposure. Important advantages of the oral poliovirus vaccine include its ability to induce mucosal immunity, and its safety, affordability and documented efficacy in both developed and developing nations. Recombinant Mengo viruses may provide an alternative approach for the induction of mucosal immunity, as their application would not be limited by prior vaccination against poliovirus. In these studies, recombinant polioviruses and Mengo viruses that express HIV and SIV antigens will be used to inoculate rhesus macaques and cynomolgus monkeys, and their abilities to elicit both cellular and secretory immune responses on mucosal surfaces will be evaluated in detail. Should the recombinant picornavirus vaccines expressing SIV antigens elicit strong mucosal immune responses, either alone or in combination with systemic administration of recombinant SIV proteins, vaccinated animals will be challenged by instillation of virulent SIV onto the vaginal mucosa. Knowledge gained from these studies may add to our understanding of genital mucosal immunity in primates, the mucosal immune response to HIV and SIV antigens and, most importantly, to ongoing efforts to contain the AIDS pandemic through the development of an effective vaccine to prevent HIV transmission.